Veterans are at increased risk for developing anxiety disorders - particularly posttraumatic stress disorder (PTSD) -- in the aftermath of combat and service. Risk is conceptualized as genetic and epigenetic factors influencing vulnerability interacting with environmental stressors, coping strategies and availability of support. Avoidance, acquired behavioral and emotional adjustments in the face of aversive stimuli, concepts and memories, traces the course of anxiety disorders and is a critical component of PTSD. Our basic science research program is developing an animal model for understanding the role of vulnerability in avoidance learning. Inbred Wistar-Kyoto rats are stress sensitive and acquire active avoidance response faster and to a higher degree than outbred Sprague-Dawley rats. We have identified a critical feature that may explain one source of faster acquisition in WKY rats; the presence of an explicit cue during periods of non-threat, which may be encoded as an explicit signal safety signal or perceived as an additional aversive stimulus. Accordingly, AIM 1 will determine why the explicit visual cue presented during the non-threat inter-trial interval facilitates avoidance acquisition in WKY rats. AIM 2 will expose the neurobiological source of the vulnerability focusing on aspects of the medial prefrontal cortex (infralimbic, prelimbic, and anterior cingulate cortices), areas known to assess threat versus safety and avoidance learning. Consequently, this area is also implicated in causing anxiety disorders. Thus, our program is designed to expose one source of risk for the development of anxiety disorders and PTSD in particular. For the vulnerable, the processing of safety versus threat escalates normal avoidance and coping to a pathological level which is resistant to extinction and treatment. Counteracting the neurobiological processes sub-serving enhanced processing of threat and safety in the medial prefrontal cortex will reduce avoidance to tolerable levels. PUBLIC HEALTH RELEVANCE: Narrative Anxiety disorders, including post-traumatic stress disorder, are a significant mental health issue for a significant proportion of military service veterans. Individuals with behaviorally-inhibited temperaments are especially vulnerable to developing these anxiety disorders following exposure to stressors. Avoidance, whether cognitive or behavioral, is a common symptom across all anxiety disorders. Our hypothesis is that the behaviorally inhibited are vulnerable to developing anxiety disorders because they are more akin to learning avoidance behaviors, while also being more resistant to extinguishing those behaviors once acquired. This program is focused on identifying the neural processes that facilitate avoidance learning in those with a behaviorally-inhibited temperament; specifically as they pertain to the role perceived threatening stimuli and safety signals in the environment have in influencing this acquisition process.